A copper-catalyzed sulfonylative C–H bond functionalization from sulfur dioxide and aryldiazonium tetrafluoroborates

Abstract

Sulfonylative C–H bond functionalization through a copper-catalyzed three-component reaction of 8-aminoquinoline amides, DABCO·(SO₂)₂ and aryldiazonium tetrafluoroborates is developed. Excellent selectivity in the para-position is observed for this copper-catalyzed transformation. This reaction is triggered by a copper-chelated complex via the coordination of the copper catalyst with the substrate and arylsulfonyl radical generated in situ, thus providing 5-sulfonyl-8-aminoquinoline amides in moderate to good yields.

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Introduction

So far, C–H bond functionalizations catalyzed by transition metals have made significant progress.¹ Diverse directing groups in transition metal-catalyzed C–H bond functionalizations have been developed.² Recently, we have been interested in the synthesis of sulfones, due to their importance in pharmaceuticals and materials.³ Usually, sulfinic acids and their salts were used as the source of the sulfonyl group for the formation of sulfones.⁴ For instance, Manolikakes and co-workers described the generation of aryl sulfones through a para-selective C–H functionalization of 1-isoquinoline carboxamides with sulfinic acid salts.⁵ This transformation was achieved by using a catalytic amount of copper(II) acetate and a stoichiometric amount of Mn(OAc)₃ as the oxidant. Other examples for the copper-catalyzed remote sulfonylation of 8-aminoquinolines by using sulfonyl chlorides or sulfinic acid salts have also been reported (Scheme 1, eqn (a)).⁶ A chelated complex from the metal catalyst and 8-aminoquinoline⁷ was proposed as the key intermediate for successful transformation through a single electron transfer. In the past few years, we have been involved in the preparation of sulfonyl compounds by using sulfur dioxide as the starting material.^8,9 Approaches including transition metal catalysis and a radical process have been developed. However, there are few reports for the sulfonylation of C–H bonds with the insertion of sulfur dioxide.^8e Prompted by the advancement of sulfur dioxide insertion chemistry,¹⁰ we envisioned that the para-selective C–H functionalization of 1-isoquinoline carboxamides with sulfur dioxide would be feasible under proper conditions via a copper-chelated complex of 8-aminoquinoline (Scheme 1, eqn (b)). Additionally, we postulated that the stoichiometric amount of oxidant as reported by Manolikakes⁵ and others⁶ would be avoided for the sulfonylative C–H bond functionalization with sulfur dioxide. Therefore, a broad reaction scope would be expected by using sulfur dioxide for the introduction of a sulfonyl group.

Scheme 1 A proposed route for the copper-catalyzed C–H bond sulfonylation with the insertion of sulfur dioxide.

Since the discovery of delivering arysulfonyl radicals from aryldiazonium tetrafluoroborates and DABCO·(SO₂)₂ ¹¹ under mild conditions,^8a diverse sulfonyl compounds have been prepared by using this strategy.⁹ We conceived that the para-selective C–H functionalization of 1-isoquinoline carboxamides with sulfur dioxide could be achieved as well through sulfonyl radicals. Encouraged by Manolikakes's work as described above,⁵ we reasoned that the combination of copper catalysis and sulfur dioxide would provide the sulfonylative products through a para-selective C–H functionalization of 1-isoquinoline carboxamides. Therefore, we started to consider the possible transformation of 1-isoquinoline carboxamides with arylsulfonyl radicals generated in situ.

From the mechanistic point of view for the copper-catalyzed C–H bond sulfonylation, we proposed a three-component reaction of 8-aminoquinoline amide 1, aryldiazonium tetrafluoroborate 2, and the sulfur dioxide surrogate of DABCO·(SO₂)₂3, which is shown in Scheme 2. We reasoned that Cu(II) would coordinate with 8-aminoquinoline amide 1 leading to a chelated complex A.⁵ The arylsulfonyl radical^8a generated in situ from the combination of aryldiazonium tetrafluoroborate 2 and DABCO·(SO₂)₂3 would undergo addition to the aromatic ring of 8-aminoquinoline 1 to afford the intermediate B. Then dehydrogenation of the intermediate B would provide the intermediate C. A subsequent single electron transfer (SET) between the intermediate C and tertiary amine cation radical would give rise to the desired sulfone 4. With these considerations, we started to investigate the feasibility of the direct sulfonylation of the C–H bond with sulfur dioxide.

Scheme 2 A plausible mechanism of the copper-catalyzed C–H bond sulfonylation with the insertion of sulfur dioxide.

Results and discussion

Since the direct sulfonylation of the C–H bond starting from sulfinic acids and their salts in the presence of copper salts would provide the site-selective product in the para-position of an amide,^5,6 we therefore examined the copper-catalyzed reaction of N-(quinolin-8-yl)benzamide 1a, 4-methylphenyldiazonium tetrafluoroborate 2a and DABCO·(SO₂)₂3. As expected, the corresponding product 4a was obtained in 50% yield when the reaction was catalyzed by copper(II) acetate in DCE (Table 1, entry 1). This result also indicated the excellent selectivity controlled by transition metal catalysis. The yield was inferior when copper(II) chloride or copper(II) bromide was used as the catalyst (Table 1, entries 2 and 3). Less efficiency was observed when the reaction worked in other solvents (Table 1, entries 4–6). Temperature was further screened, and the reaction afforded the desired product 4a in 49% yield at 60 °C (Table 1, entry 8). The yield could increase to 60% when the reaction concentration was changed (Table 1, entry 10). A control experiment without the addition of the copper catalyst failed to provide the corresponding product (Table 1, entry 12). We also examined the reaction by using potassium metabisulfite (K₂S₂O₅) as the source of sulfur dioxide. However, the transformation was not effective, and only a trace amount of product was detected (data not shown in Table 1).

Table 1 Initial studies for the copper-catalyzed reaction of N-(quinolin-8-yl)benzamide 1a, 4-methylphenyldiazonium tetrafluoroborate 2a and DABCO·(SO₂)₂3 ^a

Entry	Additive	Solvent	Temp. (°C)	Yield^b (%)
a Reaction conditions: N-(quinolin-8-yl)benzamide 1a (0.2 mmol), 4-methylphenyldiazonium tetrafluoroborate 2a (0.4 mmol), DABCO·(SO2)2 (1.5 equiv.), copper catalyst (10 mol%), solvent (2.0 mL). b Isolated yield based on N-(quinolin-8-yl)benzamide 1a. c DCE 1.0 mL. d DCE 4.0 mL.
1	Cu(OAc)2	DCE	70	50
2	CuBr	DCE	70	Trace
3	CuCl2	DCE	70	18
4	Cu(OAc)2	MeCN	70	Trace
5	Cu(OAc)2	DMF	70	Trace
6	Cu(OAc)2	1,4-Dioxane	70	40
7	Cu(OAc)2	DCE	50	44
8	Cu(OAc)2	DCE	60	49
9	Cu(OAc)2	DCE	80	41
10^c	Cu(OAc)2	DCE	60	60
11^d	Cu(OAc)2	DCE	60	47
12	—	DCE	60	NR

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We further evaluated the copper-catalyzed remote C–H bond sulfonylation under optimal reaction conditions, and the results are shown in Table 2. Firstly, an array of aryldiazonium tetrafluoroborates was investigated. We could see that the reactions worked well, leading to the desired products in moderate to good yield. For instance, the use of 2-chlorophenyldiazonium tetrafluoroborate afforded the product 4e in 72% yield. Moreover, a strong electron-donating functional group such as methoxy was also compatible, affording compounds 4h and 4i in 61% and 54% yields, respectively. However, the reaction was less effective when 4-bromophenyldiazonium tetrafluoroborate was used, and only 26% yield of the desired product 4f could be isolated.

Table 2 Scope exploration of the copper-catalyzed C–H bond sulfonylation with the insertion of sulfur dioxide^a

a Isolated yield based on aryldiazonium tetrafluoroborate 1.

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In the meantime, various 8-aminoquinoline amides 1 featuring electron-withdrawing or electron-donating groups were examined. It was found that methyl, methoxy, trifluoromethyl, fluoro, chloro, bromo and tert-butyl were all tolerated, and the corresponding products were obtained in moderate to good yields (4l–4t). Additionally, heteroaryl-substituted 8-aminoquinoline amides worked efficiently as well, giving rise to compounds 4u and 4v in good yields, while the reaction of cyclohexyl-substituted 8-aminoquinoline showed a less successful result (4w, 47% yield).

To gain a deeper insight into the mechanism of the copper-catalyzed remote C–H bond sulfonylation, 2-(allyloxy)phenyldiazonium tetrafluoroborate 5 was used to react with N-(quinolin-8-yl)benzamide 1a and DABCO·(SO₂)₂3 under the standard conditions (Scheme 3). Compound 6 with a dihydrobenzofuran skeleton was isolated in 40% yield (Scheme 3, eqn (a)). Additionally, the transformation was completely terminated with the addition of 2.0 equiv. of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) into the reaction system (Scheme 3, eqn (b)). These two experimental results suggested that the reaction experienced a radical process.

Scheme 3 Mechanism studies for the copper-catalyzed C–H bond sulfonylation with the insertion of sulfur dioxide.

Conclusions

In conclusion, we have reported a direct sulfonylation of C–H bonds with the insertion of sulfur dioxide through a copper-catalyzed three-component reaction of 8-aminoquinoline amides 1, aryldiazonium tetrafluoroborates 2, and the sulfur dioxide surrogate of DABCO·(SO₂)₂3. Excellent selectivity in the para-position is observed for this copper-catalyzed transformation. This reaction is triggered by a copper-chelated complex via the coordination of the copper catalyst with the substrate and an arylsulfonyl radical generated in situ, thus providing 5-sulfonyl-8-aminoquinoline amides in moderate to good yields. Further studies for C–H functionalization with the insertion of sulfur dioxide are under exploration in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (No. 21672037 and 21532001) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data, copies of ¹H and ¹³C NMR spectra. See DOI: 10.1039/c7qo00866j

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